Chronic sleep loss is a major public health issue, since quality sleep is imperative for good health. Insufficient sleep can lead to or exacerbate neurological conditions such as stroke, epilepsy, and neurodegenerative disorders like Parkinson's and Alzheimer's disease. It is becoming increasing clear that men and women sleep differently, as women are twice as likely to report some form of sleep disruption. Data from a number of species, including humans, strongly implicate a role for gonadal hormones, especially estrogens, in the modulation of sleep. Rodent models have shown that estradiol (E2) attenuates rapid eye movement (REM) sleep; however, the mechanism is unclear. Mounting evidence in our lab suggests that E2 may inhibit the sleep-active circuitry, specifically in the median nucleus of the preoptic nucleus (MnPN) of the hypothalamus. Our preliminary data show that E2 reduces the activational state of the MnPN during the quiescent phase. During sleep, the GABAergic neurons in the MnPN inhibit a downstream target, the lateral hypothalamus (LH). The LH contains hypocretin, a neuropeptide intimately involved in arousal as well as inhibition of REM sleep. Thus, our overarching hypothesis is that E2 suppresses activation of MnPN neurons to initiate downstream changes in the sleep circuitry leading to an attenuation of REM sleep. To investigate this hypothesis, we first aim to determine if E2-mediated suppression of REM sleep requires estrogenic action in the MnPN. Then, we will test whether E2-mediated inhibition of MnPN neurons results in the activation of hypocretinergic neurons in the LH. Finally, we will determine whether E2 increases signaling of the hypocretin system to attenuate REM sleep. We will use a multidisciplinary approach by combining behavioral, neuroanatomical, cellular and molecular techniques. Some of these include, micro-infusion of pharmacological antagonists and siRNA, immunocytochemistry, quantitative RT-PCR, and sleep behavior analysis. Advancing our understanding of the mechanisms underlying ovarian hormonal modulation of sleep will lead to new perspectives on the roots of sleep disturbance in the female brain. Ultimately, this may serve to uncover novel drug targets for the treatment of sleep disruptions in women. PUBLIC HEALTH RELEVANCE: Chronic sleep loss can lead to or increase the severity of neurological conditions like stroke, epilepsy, and neurodegenerative disorders. Women tend to report sleep disruptions more often than men and these symptoms typically coincide with changes in the ovarian hormonal milieu. This proposal aims to address how ovarian hormones influence the mechanisms underlying sleep/wake behaviors to provide a better understanding of the origins of sleep disruptions in the female brain and how sleep disturbances in women can be treated.